Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Oxidative stress as an iceberg in carcinogenesis and cancer biology. Reviewed

Toyokuni S.

Arch Biochem Biophys. 2016 Apr 1;595:46-9. Vol. 595 page： 46-9 2016.4

Oxidative stress as an iceberg in carcinogenesis and cancer biology. Reviewed International journal

Toyokuni S

Arch Biochem Biophys. 2016 Apr 1;595:46-9. Vol. 595 page： 46-9 2016.4

Tribute issue: Helmut Sies and oxidative stress: Venit, vidit, vicit Reviewed International journal

Forman H.

Archives of Biochemistry and Biophysics Vol. 595 2016.4

Redox cycling metals: Pedaling their roles in metabolism and their use in the development of novel therapeutics.

Kalinowski DS, Stefani C, Toyokuni S, Ganz T, Anderson GJ, Subramaniam NV, Trinder D, Olynyk JK, Chua A, Jansson PJ, Sahni S, Lane DJ, Merlot AM, Kovacevic Z, Huang ML, Lee CS, Richardson DR.

Biochim Biophys Acta. Vol. 1863 ( 4 ) page： 727-748 2016.4

Redox cycling metals: Pedaling their roles in metabolism and their use in the development of novel therapeutics. International journal

Danuta S Kalinowski, Christian Stefani, Shinya Toyokuni, Tomas Ganz, Gregory J Anderson, Nathan V Subramaniam, Debbie Trinder, John K Olynyk, Anita Chua, Patric J Jansson, Sumit Sahni, Darius J R Lane, Angelica M Merlot, Zaklina Kovacevic, Michael L H Huang, C Soon Lee, Des R Richardson

Biochimica et biophysica acta Vol. 1863 ( 4 ) page： 727 - 48 2016.4

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Essential metals, such as iron and copper, play a critical role in a plethora of cellular processes including cell growth and proliferation. However, concomitantly, excess of these metal ions in the body can have deleterious effects due to their ability to generate cytotoxic reactive oxygen species (ROS). Thus, the human body has evolved a very well orchestrated metabolic system that keeps tight control on the levels of these metal ions. Considering their very high proliferation rate, cancer cells require a high abundance of these metals compared to their normal counterparts. Interestingly, new anti-cancer agents that take advantage of the sensitivity of cancer cells to metal sequestration and their susceptibility to ROS have been developed. These ligands can avidly bind metal ions to form redox active metal complexes, which lead to generation of cytotoxic ROS. Furthermore, these agents also act as potent metastasis suppressors due to their ability to up-regulate the metastasis suppressor gene, N-myc downstream regulated gene 1. This review discusses the importance of iron and copper in the metabolism and progression of cancer, how they can be exploited to target tumors and the clinical translation of novel anti-cancer chemotherapeutics. (C) 2016 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.bbamcr.2016.01.026

Role of hemoglobin and transferrin in multi-wall carbon nanotube-induced mesothelial injury and carcinogenesis. Reviewed

Wang Y, Okazaki Y, Shi L, Kohda H, Tanaka M, Taki K, Nishioka T, Hirayama T, Nagasawa H, Yamashita Y, Toyokuni S.

Cancer Sci. Vol. 107 ( 3 ) page： 250-257 2016.3

Pain-reducing anesthesia prevents oxidative stress in human term placenta. Reviewed

Tsuzuki Y, Yamashita Y, Hattori Y, Hua Li G, Akatsuka S, Kotani T, Kikkawa F, Naiki-Ito A, Takahashi S, Nishiwaki K, Toyokuni S.

J Clin Biochem Nutr. Vol. 58 ( 2 ) page： 156-60 2016.3

Pain-reducing anesthesia prevents oxidative stress in human term placenta International journal

Tsuzuki Yoko, Yamashita Yoriko, Hattori Yuka, Hua Li Guang, Akatsuka Shinya, Kotani Tomomi, Kikkawa Fumitaka, Naiki-Ito Aya, Takahashi Satoru, Nishiwaki Kimitoshi, Toyokuni Shinya

Journal of Clinical Biochemistry and Nutrition Vol. 58 ( 2 ) page： 156 - 60 2016.3

Language：English Publishing type：Research paper (scientific journal) Publisher：SOCIETY FOR FREE RADICAL RESEARCH JAPAN

Anesthesia is sometimes used for the reduction of maternal pain in normal human term labor, but whether the drugs affect oxidative stress remains unclear. The placenta serves as an interface between the maternal and fetal vasculature. In this study, we immunohistochemically analyzed two markers for oxidative stress, namely 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal–modified proteins (HNE), using placentas from 21 cases of normal tansvaginal delivery (V group), 20 Caesarean sections (C group), and 17 normal transvaginal deliveries with epidural anesthesia (E group). 8-OHdG staining in the nuclei of trophoblasts lining the chorionic villi was significantly stronger in the V group either compared with the C or E group (p<0.001), without significant differences in the C and E groups (p = 0.792). Moderate to intense staining by HNE of the intravascular serum of chorionic villi vasculature was frequently observed in the placentas from the V group, but less frequently of those in either C or E groups (p<0.001), nor the p value comparing the C and E groups was significant (p = 0.128) for HNE staining. Our results suggest that although the role of oxidative stress and its influences on fetal state in the placenta in labor remains unclear, it seems to be lessened by epidural anesthesia.

DOI： 10.3164/jcbn.15-138

Role of hemoglobin and transferrin in multi-wall carbon nanotube-induced mesothelial injury and carcinogenesis. International journal

Yue Wang, Yasumasa Okazaki, Lei Shi, Hiro Kohda, Minoru Tanaka, Kentaro Taki, Tomoki Nishioka, Tasuku Hirayama, Hideko Nagasawa, Yoriko Yamashita, Shinya Toyokuni

Cancer science Vol. 107 ( 3 ) page： 250 - 7 2016.3

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Multi-wall carbon nanotubes (MWCNT) are a form of flexible fibrous nanomaterial with high electrical and thermal conductivity. However, 50-nm MWCNT in diameter causes malignant mesothelioma (MM) in rodents and, thus, the International Agency of Research on Cancer has designated them as a possible human carcinogen. Little is known about the molecular mechanism through which MWCNT causes MM. To elucidate the carcinogenic mechanisms of MWCNT in mesothelial cells, we used a variety of lysates to comprehensively identify proteins specifically adsorbed on pristine MWCNT of different diameters (50 nm, NT50; 100 nm, NT100; 150 nm, NT150; and 15 nm/tangled, NTtngl) using mass spectrometry. We identified >400 proteins, which included hemoglobin, histone, transferrin and various proteins associated with oxidative stress, among which we selected hemoglobin and transferrin for coating MWCNT to further evaluate cytotoxicity, wound healing, intracellular catalytic ferrous iron and oxidative stress in rat peritoneal mesothelial cells (RPMC). Cytotoxicity to RPMC was observed with pristine NT50 but not with NTtngl. Coating NT50 with hemoglobin or transferrin significantly aggravated cytotoxicity to RPMC, with an increase in cellular catalytic ferrous iron and DNA damage also observed. Knockdown of transferrin receptor with ferristatin II decreased not only NT50 uptake but also cellular catalytic ferrous iron. Our results suggest that adsorption of hemoglobin and transferrin on the surface of NT50 play a role in causing mesothelial iron overload, contributing to oxidative damage and possibly subsequent carcinogenesis in mesothelial cells. Uptake of NT50 at least partially depends on transferrin receptor 1. Modifications of NT50 surface may decrease this human risk.

DOI： 10.1111/cas.12865

Neuroprotective potential of molecular hydrogen against perinatal brain injury via suppression of activated microglia. Reviewed

Imai K, Kotani T, Tsuda H, Mano Y, Nakano T, Ushida T, Li H, Miki R, Sumigama S, Iwase A, Hirakawa A, Ohno K, Toyokuni S, Takeuchi H, Mizuno T, Suzumura A, Kikkawa F.

Free Radic Biol Med. Vol. 91 page： 154-163 2016.2

Neuroprotective potential of molecular hydrogen against perinatal brain injury via suppression of activated microglia International journal

Kenji Imai, Tomomi Kotani, Hiroyuki Tsuda, Yukio Mano, Tomoko Nakano, Takafumi Ushida, Hua Li, Rika Miki, Seiji Sumigama, Akira Iwase, Akihiro Hirakawa, Kinji Ohno, Shinya Toyokuni, Hideyuki Takeuchi, Tetsuya Mizuno, Akio Suzumura, Fumitaka Kikkawa

FREE RADICAL BIOLOGY AND MEDICINE Vol. 91 page： 154 - 63 2016.2

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Exposure to inflammation in utero is related to perinatal brain injury, which is itself associated with high rates of long-term morbidity and mortality in children. Novel therapeutic interventions during the perinatal period are required to prevent inflammation, but its pathogenesis is incompletely understood. Activated microglia are known to play a central role in brain injury by producing a variety of pro-inflammatory cytokines and releasing oxidative products. The study is aimed to investigate the preventative potential of molecular hydrogen (H-2), which is an antioxidant and anti-inflammatory agent without mutagenicity. Pregnant ICR mice were injected with lipopolysaccharide (LPS) intraperitoneally on embryonic day 17 to create a model of perinatal brain injury caused by prenatal inflammation. In this model, the effect of maternal administration of hydrogen water (HW) on pups was also evaluated. The levels of pro-inflammatory cytokines, oxidative damage and activation of microglia were determined in the fetal brains. H-2 reduced the LPS-induced expression of pro-inflammatory cytokines, oxidative damage and microglial activation in the fetal brains. Next, we investigated how H-2 contributes to neuroprotection, focusing on microglia, using primary cultured microglia and neurons. H-2 prevented LPS- or cytokine-induced generation of reactive oxidative species by microglia and reduced LPS-induced microglial neurotoxicity. Finally, we identified several molecules influenced by H-2, involved in the process of activating microglia. These results suggested that H-2 holds promise for the prevention of inflammation related to perinatal brain injury. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.freeradbiomed.2015.12.015

Plasma with high electron density and plasma-activated medium for cancer treatment Reviewed International journal

Tanaka Hiromasa, Mizuno Masaaki, Ishikawa Kenji, Kondo Hiroki, Takeda Keigo, Hashizume Hiroshi, Nakamura Kae, Utsumi Fumi, Kajiyama Hiroaki, Kano Hiroyuki, Okazaki Yasumasa, Toyokuni Shinya, Akiyama Shin'ichi, Maruyama Shoichi, Yamada Suguru, Kodera Yasuhiro, Kaneko Hiroki, Terasaki Hiroko, Hara Hirokazu, Adachi Tetsuo, Iida Machiko, Yajima Ichiro, Kato Masashi, Kikkawa Fumitaka, Hori Masaru

CLINICAL PLASMA MEDICINE Vol. 3 ( 2 ) page： 72 - 76 2015.12

Ovarian endometriosis-associated stromal cells reveal persistently high affinity for iron. Reviewed

Mori M, Ito F, Shi L, Wang Y, Ishida C, Hattori Y, Niwa M, Hirayama T, Nagasawa H, Iwase A, Kikkawa F, Toyokuni S.

Redox Biol. Vol. 6 page： 578-586 2015.12

Cancer therapy using non-thermal atmospheric pressure plasma with ultra-highelectron density International journal

H. Tanaka, M. Mizuno, S. Toyokuni, S. Maruyama, Y. Kodera, H. Terasaki, T. Adachi, M. Kato, F. Kikkawa, M. Hori

Phys Plasmas Vol. 22 ( 12 ) page： 122004 2015.12

Ovarian endometriosis-associated stromal cells reveal persistently high affinity for iron International journal

Masahiko Mori, Fumiya Ito, Lei Shi, Yue Wang, Chiharu Ishida, Yuka Hattori, Masato Niwa, Tasuku Hirayama, Hideko Nagasawa, Akira Iwase, Fumitaka Kikkawa, Shinya Toyokuni

REDOX BIOLOGY Vol. 6 page： 578 - 586 2015.12

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Ovarian endometriosis is a recognized risk for infertility and epithelial ovarian cancer, presumably due to iron overload resulting from repeated hemorrhage. To find a clue for early detection and prevention of ovarian endometriosis-associated cancer, it is mandatory to evaluate catalytic (labile) ferrous iron (catalytic Fe(II)) and to study iron manipulation in ovarian endometriotic lesions. By the use of tissues from women of ovarian endometriosis as well as endometrial tissue from women with and without endometriosis, we for the first time performed histological analysis and cellular detection of catalytic Fe(II) with a specific fluorescent probe (HMRhoNox-M), and further evaluated iron transport proteins in the human specimens and in co-culture experiments using immortalized human eutopic/ectopic endometrial stromal cells (ESCs) in the presence or absence of epithelial cells (EpCs). The amounts of catalytic Fe(II) were higher in ectopic endometrial stromal cells (ecESCs) than in normal eutopic endometrial stromal cells (n-euESCs) both in the tissues and in the corresponding immortalized ESCs. ecESCs exhibited higher transferrin receptor 1 expression both in vivo and in vitro and lower ferroportin expression in vivo than n-euESCs, leading to sustained iron uptake. In co-culture experiments of ESCs with iron-loaded EpCs, ecESCs received catalytic ferrous iron from EpCs, but n-euESCs did not. These data suggest that ecESC play a protective role for cancer-target epithelial cells by collecting excess iron, and that these characteristics are retained in the immortalized ecESCs. (C) 2015 The Authors. Published by Elsevier B.V.

DOI： 10.1016/j.redox.2015.10.001

Effects of Plasma-Activated Medium on Cells

TANAKA Hiromasa, MIZUNO Masaaki, TOYOKUNI Shinya, MARUYAMA Shoichi, KODERA Yasuhiro, ADACHI Tetsuo, TERASAKI Hiroko, KATO Masashi, KIKKAWA Fumitaka, HORI Masaru

Vol. 91 ( 12 ) page： 776 - 779 2015.12

Effects of Plasma-Activated Medium on Cells

TANAKA Hiromasa, MIZUNO Masaaki, TOYOKUNI Shinya, MARUYAMA Shoichi, KODERA Yasuhiro, ADACHI Tetsuo, TERASAKI Hiroko, KATO Masashi, KIKKAWA Fumitaka, HORI Masaru

Vol. 91 ( 12 ) page： 776 - 779 2015.12

Maternal molecular hydrogen administration on lipopolysaccharide-induced mouse fetal brain injury Reviewed International journal

Tomoko Nakano, Tomomi Kotani, Yukio Mano, Hiroyuki Tsuda, Kenji Imai, Takafumi Ushida, Hua Li, Rika Miki, Seiji Sumigama, Yoshiaki Sato, Akira Iwase, Akihiro Hirakawa, Masato Asai, Shinya Toyokuni, Fumitaka Kikkawa

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION Vol. 57 ( 3 ) page： 178 - 182 2015.11

Publishing type：Research paper (scientific journal) Publisher：JOURNAL CLINICAL BIOCHEMISTRY & NUTRITION

Fetal brain injury is often related to prenatal inflammation; however, there is a lack of effective therapy. Recently, molecular hydrogen (H-2), a specific antioxidant to hydroxyl radical and peroxynitrite, has been reported to have anti-inflammatory properties. The aim of this study was to investigate whether maternal H-2 administration could protect the fetal brain against inflammation. Pregnant C3H/HeN mice received an intraperitoneal injection of lipopolysaccharide (LPS) on gestational day 15.5 and were provided with H2 water for 24 h prior to LPS injection. Pup brain samples were collected on gestational day 16.5, and the levels of apoptosis and oxidative damage were evaluated using immunohistochemistry. Interleukin-6 (IL-6) levels were examined using real-time PCR. The levels of apoptosis and oxidative damage, as well as the levels of IL-6 mRNA, increased significantly when the mother was injected with LPS than that in the control group. However, these levels were significantly reduced when H2 was administered prior to the LPS-injection. Our results suggest that LPS-induced apoptosis, oxidative damage and inflammation in the fetal brain were ameliorated by maternal H2 administration. Antenatal H2 administration might protect the premature brain against maternal inflammation.

DOI： 10.3164/jcbn.15-90

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Maternal molecular hydrogen administration on lipopolysaccharide-induced mouse fetal brain injury. Reviewed

Nakano T, Kotani T, Mano Y, Tsuda H, Imai K, Ushida T, Li H, Miki R, Sumigama S, Sato Y, Iwase A, Hirakawa A, Asai M, Toyokuni S, Kikkawa F.

J Clin Biochem Nutr. Vol. 57 ( 3 ) page： 178-182 2015.11

A trial to find appropriate animal models of dichloropropaneinduced cholangiocarcinoma based on the hepatic distribution of glutathione S-transferases

Zhang Lingyi, Zong Cai, Ichihara Sahoko, Naito Hisao, Toyokuni Shinya, Kumagai Shinji, Ichihara Gaku

JOURNAL OF OCCUPATIONAL HEALTH Vol. 57 ( 6 ) page： 548 - 554 2015.11

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Papers - TOYOKUNI Shinya